Pregnancy-associated plasma protein A (PAPP-A) is an insulin-like growth factor binding protein 4 (IGFBP-4) protease that can function to increase local IGF-I bioavailability. Aside from its assumed role during pregnancy, in vitro and in vivo studies have indicated roles for PAPP-A in IGF-I-mediated wound healing, vascular repair and bone formation. As bone morphogenetic protein 2 (BMP-2) is known to up-regulate Igf-I gene expression, we hypothesized that PAPP-A may be involved in BMP-2 mechanisms in bone formation. To test this hypothesis, we quantified gene expression of Papp-A in response to BMP-2 treatment and Runx2, Osterix (Osx) and Igf-I in response to PAPP-A protein treatment in human adult mesenchymal stem cells (hMSC). Our results demonstrate that BMP-2 directly up-regulated Papp-A gene and protein expression. Purified PAPP-A protein directly up-regulated Runx2 and Igf-I gene expression, but not Osx. When added in combination with recombinant human BMP-2, PAPP-A increased matrix mineralization in the absence of dexamethasone. PAPP-A further demonstrated an angiogenic effect in the chick chorioallontoic membrane (CAM) which implicates a critical developmental role and possible therapeutic potential. Our findings suggest that PAPP-A functions in the formation of mineralized tissues through direct up-regulation of key genes. Further, PAPP-A is involved in the formation of new blood vessels which is essential for proper bone regeneration.